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An interplay of structure and intrinsic disorder in the functionality of peptidylarginine deiminases, a family of key autoimmunity-related enzymes

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Abstract

Citrullination is a post-translation modification of proteins, where the proteinaceous arginine residues are converted to non-coded citrulline residues. The immune tolerance to such citrullinated protein can be lost, leading to inflammatory and autoimmune diseases. Citrullination is a chemical reaction mediated by peptidylarginine deiminase enzymes (PADs), which are a family of calcium-dependent cysteine hydrolase enzymes that includes five isotypes: PAD1, PAD2, PAD3, PAD4, and PAD6. Each PAD has specific substrates and tissue distribution, where it modifies the arginine to produce a citrullinated protein with altered structure and function. All mammalian PADs have a sequence similarity of about 70–95%, whereas in humans, they are 50–55% homologous in their structure and amino acid sequences. Being calcium-dependent hydrolases, PADs are inactive under the physiological level of calcium, but could be activated due to distortions in calcium homeostasis, or when the cellular calcium levels are increased. In this article, we analyze some of the currently available data on the structural properties of human PADs, the mechanisms of their calcium-induced activation, and show that these proteins contain functionally important regions of intrinsic disorder. Citrullination represents an important trigger of multiple physiological and pathological processes, and as a result, PADs are recognized to play a number of important roles in autoimmune diseases, cancer, and neurodegeneration. Therefore, we also review the current state of the art in the development of PAD inhibitors with good potency and selectivity.

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Alignment was conducted by the MultiProt algorithm (http://www.bioinfo3d.cs.tau.ac.il/MultiProt/) [138]. Structural representation was developed using the VMD platform [184]

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Acknowledgements

We are thankful to Alexey V. Uversky for careful reading and editing of this manuscript.

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Authors and Affiliations

  1. Biological Sciences Department, Faculty of Science, King Abdulaziz University, P.O. Box 80203, Jeddah, 21589, Saudi Arabia

    Mohammed Alghamdi, Khaled A. Al Ghamdi, Vladimir N. Uversky & Elrashdy M. Redwan

  2. Laboratory Department, University Medical Services Center, King Abdulaziz University, P.O. Box 80200, Jeddah, 21589, Saudi Arabia

    Mohammed Alghamdi

  3. Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh, UP, India

    Rizwan H. Khan

  4. Protein Research Group, Institute for Biological Instrumentation of the Russian Academy of Sciences, 7 Institutskaya Str., 142290, Pushchino, Moscow region, Russia

    Vladimir N. Uversky

  5. Department of Molecular Medicine and USF Health Byrd Alzheimer’s Research Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA

    Vladimir N. Uversky

  6. Therapeutic and Protective Proteins Laboratory, Protein Research Department, Genetic Engineering and Biotechnology Research Institute, City for Scientific Research and Technology Applications, New Borg EL-Arab, Alexandria, 21934, Egypt

    Elrashdy M. Redwan

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Alghamdi, M., Al Ghamdi, K.A., Khan, R.H. et al. An interplay of structure and intrinsic disorder in the functionality of peptidylarginine deiminases, a family of key autoimmunity-related enzymes. Cell. Mol. Life Sci. 76, 4635–4662 (2019). https://doi.org/10.1007/s00018-019-03237-8

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